Oropharyngeal cancer is rapidly increasing in incidence in the veteran population, fueled largely by exposure to the human papilloma virus (HPV). Although survival for oropharyngeal squamous cell carcinoma associated with the human papilloma virus (HPV+OPSCC) is excellent in the general population, it remains dismal in the veteran population, with nearly 1 in 2 patients dying of their disease within 5 years of diagnosis. This disproportionally poor survival is thought to be driven in part by tumors which are less responsive to chemo-radiation treatment regimens. Preliminary data from our group and others suggests this decreased treatment response may be in part driven by tobacco exposure, which is extremely prevalent among Veterans with HPV+OPSCC. The hypothesized mechanism of action is a tobacco induced, immunosuppressive environment which inhibits the normal anti-tumor activity of lymphocytes and other immune cells during cancer treatment. In the current proposal, we will first characterize and quantify the relative effect of tobacco exposure on survival in Veterans with HPV+OPSCC (Aim 1). This is critical in light of the newly implemented 8th Edition of the AJCC Staging Manual which dramatically down-stages OPSCC based on HPV status (HPV associated vs non-HPV associated), but does not consider the potentially critical impact of tobacco exposure on survival. Given the widespread, and extensive tobacco exposure we and others have demonstrated in Veterans with OPSCC, this represents an important clinical and translational first step in potentially improving survival for Veterans with this disease. We will then characterize the Th1 T-lymphocyte and myeloid derived suppressor cell (MDSC) components of the tumor immune microenvironment (TIME) in HPV+OPSCC tumors as a function of tobacco exposure (Aim 2). This will allow us to provide support for our mechanistic hypothesis and to define the relationship between tobacco exposure and changes in the TIME of HPV+OPSCC. Finally, we will compare the TIME characteristics of HPV+OPSCC tumors which fail to respond to conventional chemo-radiation treatment regimens to the TIME of HPV+OPSCC tumors which do respond to treatment, in order to define an immune signature associated with treatment resistance in this disease site (Aim 3). Together, these experiments will allow us to: 1) define a clinically relevant effect size for tobacco exposure vis a vis HPV+OPSCC survival and 2) begin to define a mechanistic link between tobacco exposure and TIME dependent treatment response. Successful completion of the proposed research will allow us to more appropriately prognosticate survival in Veterans with HPV+OPSCC, identify patients which may be candidates for treatment escalation using immunomodulatory agents (i.e. checkpoint inhibitors) and patients which should not be enrolled in clinical trials aimed at de-escalation of chemo-radiation regimens in order to decrease normal tissue toxicity. In parallel with the proposed research, the Principal Investigator will engage in training activities designed to provide increased facility and expertise in the areas of Epidemiology and Biostatistics as well as Tumor Immunology, through a combination of formal and online course work, participation in institutional, local and national meetings and direct interactions with a Mentorship Committee with appropriate expertise in these 3 areas of cancer research.